Hypothesis

Acarbose extends lifespan preferentially in males by remodeling the gut microbiome to increase butyrate‑producing taxa, which activates the bile‑acid receptor TGR5 in intestinal epithelia and hepatocytes, thereby boosting the endocrine fibroblast growth factor 21 (FGF21) pathway. Male mice exhibit higher hepatic TGR5 signaling and androgen‑dependent upregulation of β‑Klotho, making them more responsive to butyrate‑driven FGF21 secretion, which promotes autophagy, insulin sensitivity, and stress resistance. Consequently, the male‑biased longevity effect of acarbose depends on microbiome‑derived butyrate acting through the TGR5‑FGF21 axis, independent of its glucose‑blunting activity.

Testable Predictions

1. Microbiota transfer: Germ‑free male mice receiving fecal microbiota from acarbose‑treated male donors will show increased fecal butyrate, hepatic TGR5 activation, elevated circulating FGF21, and extended median lifespan compared with recipients of female donor microbiota or vehicle controls.
2. Pharmacological blockade: Treating acarbose‑fed male mice with a TGR5 antagonist (e.g., SBI‑243) or intestinal‑specific Tgr5 knockout will abolish the lifespan extension and FGF21 rise without affecting post‑prandial glucose levels.
3. Sex‑specific signaling: Castrated males or females supplemented with testosterone will recapitulate the male‑level TGR5‑FGF21 response to acarbose‑induced microbiome shifts, linking androgen status to pathway sensitivity.
4. Glucose independence: Pair‑fed controls matched for reduced caloric intake due to acarbose will not reproduce the lifespan benefit, indicating that glucose lowering alone is insufficient.

Mechanistic Reasoning

• Acarbose‑driven enrichment of Subdoligranulum and butyrate‑producing Bacteroidaceae raises luminal butyrate (see 5 and 6).
• Butyrate is a known agonist of the G‑protein‑coupled receptor TGR5, stimulating cAMP production and downstream FGF21 secretion from intestinal L‑cells and hepatocytes (established in literature).
• Sex differences in hepatic TGR5 expression and androgen‑regulated β‑Klotho have been reported to modulate FGF21 signaling efficacy, providing a plausible basis for the observed male bias.
• The synergy with rapamycin (see 2) may stem from convergent activation of autophagy via both TGR5‑FGF21 and mTORC1 inhibition.

Falsifiability

If fecal transplants from acarbose‑treated males fail to extend lifespan in male recipients, or if TGR5 inhibition does not diminish the longevity benefit while glucose remains low, the hypothesis would be refuted, supporting an alternative primary role for direct glucose modulation or other metabolites.

Key References

[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC6413665/ [2] https://lifespan.io/news/a-drug-combo-increases-lifespan-in-mice-by-over-30/ [3] https://www.rapamycin.news/t/new-march-2026-itp-results-its-all-bad-news/23992 [4] https://pmc.ncbi.nlm.nih.gov/articles/PMC4620230/ [5] https://pmc.ncbi.nlm.nih.gov/articles/PMC5380489/ [6] https://asm.org/press-releases/2019/february/diabetes-drug-impacts-gut-microbiome [7] https://pubmed.ncbi.nlm.nih.gov/39565129/ [8] https://www.aginganddisease.org/EN/10.14336/AD.2022.0117